1. Field of the Invention
The present invention relates to the fields of molecular biology and medicine. Mesoporous silicon particles and compositions comprising them are provided for use in a variety of diagnostic and therapeutic indications. In particular, nanoparticle-loaded pSi particles for the presentation of tumor antigens and as adjuvants for anti-cancer immunity have been developed.
2. Description of Related Art
Adjuvants
Aluminum-based adjuvants, designed to enhance immune responses to antigens, were introduced in the 1920s, and 91 years later, they remain the standard adjuvant used in vaccines. Studies on new nanoparticle-based vaccines are increasing, with the advantage of combining adjuvant and antigen in a single entity. These particles are rapidly internalized by antigen-presenting cells (APC) with trafficking to lymphoid tissue for presentation to lymphocytes.
Nanotechnology
Nanotechnology pertains to synthetic, engineerable objects that are nanoscale in dimensions or have critical functioning nanoscale components, leading to novel, unique properties (Ferrari, 2005; Theis et al., 2006). These emergent characteristics arise from the material's large surface area and nanoscopic size (Riehemann, 2009). Nanotechnology now occupies a niche as a burgeoning and revolutionary field within medicine known as nanomedicine, particularly within the field of oncology (Ferrari, 2005). One of the potential benefits of nanomedicine is the creation of nanoparticle-based vectors that deliver therapeutic cargo in sufficient quantity to a target lesion to enable a selective effect. This is a daunting task for all drug molecules, owing to the highly organized array of ‘biological barriers’ that the molecules encounter (Riehemann, 2009; Jain, 1989; Jain, 1999; Sakamoto et al., 2007). The human body presents a robust defense system that is extremely effective in preventing injected chemicals, biomolecules, nanoparticles and any other foreign agents from reaching their intended destinations. Biobarriers are sequential in nature, and therefore, the probability of reaching the therapeutic objective is the product of individual probabilities of overcoming each barrier (Ferrari, 2005; Ferrari, 2009). Sequentially (with respect to intravascular injections) these comprise: 1) enzymatic degradation; 2) sequestration by phagocytes of the reticulo-endothelial system (RES) (Caliceti and Veronese, 2003; Moghimi and Davis, 1994); 3) vascular endothelia (Mehta and Malik, 2006); 4) adverse oncotic and interstitial pressures in the tumor (Stohrer et al., 2000; Less et al., 1992); 5) cellular membranes, or subcellular organelles such as the nucleus and endosomes (Torchilin, 2006; Majumdar and Mitra, 2006); and 6) molecular efflux pumps (Undevia et al., 2005). Without an effective strategy to negotiate these barriers, new or current therapeutic agents based on enhanced biomolecular selectivity may yield sub-optimal utility, simply because they reach the intended targets in very small fractions, with only 1 in 10,000 to 1 in 100,000 molecules reaching their intended site of action (Ferrari, 2005). Due to this narrow therapeutic window, marginal tolerability and considerable mortality ensue (Canal et al., 1998). Transport through different compartments and across biological barriers can be enhanced by optimization of particle size, shape, density and surface chemistry. These parameters dominate transport in the bloodstream, margination, cell adhesion, selective cellular uptake, and sub-cellular trafficking.
An early obstacle for intravascularly administered therapeutics is the endothelial wall that forms the boundary between the circulatory system and tissue specific microenvironments. Specific adherence of delivery vectors to diseased vasculature provides a key to conquering this early barrier, as does the hijacking of cells bound for the inflammatory microenvironment of the lesion. In particular, what is lacking in the prior art are compositions and methods for efficiently overcoming various bio-barriers that employ multiple levels of targeting, spatial release of secondary carriers or therapeutics, simultaneous delivery of independent systems and/or systems capable of synergistic impact.